Mitochondrial-derived reactive oxygen species (ROS) are a harmful by-product of oxygen deprivation. Cell damage from ROS exposure can be irreversible, and chronically high levels of ROS are a characteristic of the pathogenesis of many degenerative diseases and cancers. In order to mitigate the effects of ROS in hypoxic environments, oxygen-sensitive pathways have evolved that initiate adaptive responses, including a marked shift in metabolic strategy toward lactate production. These metabolic changes are supported by a wide-ranging transcriptional response to hypoxia. Many of the transcriptional responses proceed through the actions of the hypoxia-inducible factor-1 (HIF-1) pathway, but emerging evidence suggests that non-HIF-mediated pathways are also prominent in the responses and provide essential adaptive support. The regulators and upstream mediators for the non-HIF-mediated responses are not well understood, or not known at all. This project seeks to use Drosophila genetics as a tool to uncover these factors using hypoxia-sensitive sensor animals coupled to an unbiased genetic screen of the third chromosome.